First Report of Concurrent Homozygous LEP and PKHD1 Pathogenic Variants in a Child with Early-Onset Obesity and Renal Microlithiasis

Somayeh  Talaeipour; Seyedeh Zalfa  Modarresi; Elham  Shafighii

doi:10.18502/wjpn.v7i2.20452

Somayeh Talaeipour Mother and Newborn Health Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
Seyedeh Zalfa Modarresi Department of Pediatrics, Shahid Sadoughi Hospital, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
Elham Shafighii Children and Adolescents Health Research Center, Research Institute of Cellular and Molecular Science in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran

DOI: https://doi.org/10.18502/wjpn.v7i2.20452

Keywords: Leptin, Deficiency, PKHD1, Nephrocalcinosis, Consanguinity, Whole-exome sequencing

Abstract

Background: Severe early-onset obesity with hyperphagia may be caused by a monogenic disorder involving the leptin–melanocortin pathway. Leptin (LEP) deficiency is a known cause of congenital obesity, whereas PKHD1 mutations are associated with autosomal recessive polycystic kidney disease (ARPKD).

Case Presentation: We report a 20-month-old boy born to consanguineous parents with rapid weight gain since birth (current body weight of 25 kg), extreme hyperphagia, truncal obesity, acanthosis nigricans, dyslipidemia, and renal microlithiasis or nephrocalcinosis Results of endocrine and thyroid function tests were unremarkable. Renal ultrasonography revealed multiple echogenic foci, with no cystic dilatation or sonographic evidence of impaired renal function. Whole exome sequencing identified homozygous pathogenic variants in both LEP and PKHD1, consistent with autosomal recessive inheritance.

Interpretation: The LEP variant explains the early-onset severe obesity, hyperphagia, and metabolic abnormalities observed in this patient, as seen in congenital leptin deficiency. The PKHD1 variant likely accounts for the atypical renal phenotype of nephrocalcinosis without overt cystic disease and may result in a truncating frameshift. To our knowledge, this is the first report of simultaneous pathogenic LEP and PKHD1 variants in an individual.

Conclusion: The case underscores the clinical and diagnostic value of whole-genome analysis in early-onset obesity, particularly in consanguineous families where two or more recessive conditions can co-occur by chance. More comprehensive genetic evaluation should be encouraged in atypical or multisystem obesity in children to uncover composite molecular etiologies.